rs727504887

Variant names:

• chr11-47342127-C-A
• rs727504887
• NM_000256.3:c.1654G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-47342127-C-A
• chr11-47342127-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000256.3(MYBPC3):​c.1654G>T​(p.Ala552Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A552T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.53
• Publications: 1 publications found

Genes affected

MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

MYBPC3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47342127-C-A is Pathogenic according to our data. Variant chr11-47342127-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179473.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1654G>T	p.Ala552Ser	missense_variant	Exon 18 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1654G>T	p.Ala552Ser	missense_variant	Exon 18 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1654G>T	p.Ala552Ser	missense_variant	Exon 17 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1654G>T		non_coding_transcript_exon_variant	Exon 18 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000267 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Apr 04, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala552Ser variant in MYBPC3 has not been previously reported in individuals with cardiomyopathy and was absent from large population studies. Computational analyses (amino acid biochemical properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additional information is needed to fully assess the clinical significance of this variant. -

Jul 01, 2011

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted Ala552Ser (aka A552S) at the protein level and c.1654 G>T at the cDNA level. The Ala552Ser variant in the MYBPC3 gene has not been reported as a disease-causing mutation, nor is it a known benign polymorphism to our knowledge. Ala552Ser results in a non-conservative amino acid substitution of a non-polar, hydrophobic Alanine residue with a polar Serine residue at a position that is conserved across species throughout evolution. In silico analysis predicts that Ala552Ser is possibly damaging to the structure/function of the protein and disease causing. A mutation affecting a nearby residue (Met555Thr) has been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, Ala552Ser was not detected in up to 600 alleles from control individuals of Caucasian and African American ancestry, indicating it is not a common benign variant in those populations. However, we cannot rule out that this change may be a benign variant. In summary, with the clinical and molecular information available at this time, we cannot definitively determine the clinical significance of the Ala552Ser variant, although evidence suggests it may be disease-causing. The variant is found in DCM panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
CardioboostCm	Uncertain	0.12
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.94	L;.;.
PhyloP100		7.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.5	N;.;N
REVEL	Benign	0.20
Sift	Benign	0.23	T;.;T
Sift4G	Uncertain	0.012	D;D;D
Vest4		0.75
MVP		0.90
MPC		0.79
ClinPred		0.90	D
GERP RS		5.7
Varity_R		0.25
gMVP		0.63
Mutation Taster		=57/43	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727504887; hg19: chr11-47363678;